This application for a Physician Scientist Award proposes rigorous and extensive training in antigen presentation and protein chemistry as the foundation for a career in experimental immunology. To initiate such a career, an intensive laboratory experience under the direction of Dr. Jack L. Strominger will be coupled pertinent graduate level didactic work and seminar series attendance. Dr. Strominger will serve as phase I sponsor of a research proposal to investigate epitope presentation in autoimmune diabetes. Type I diabetes is an organ-specific autoimmune disease of the pancreas. Certain alleles of the histocompatibility complex (MHC) class II genes in humans, HLA-DR4 and HLA-DQ8, correlate with diabetes. The presumptive initiating autoantigen is glutamic acid decarboxylase (GAD 65). Epitopes derived from GAD 65 are recognized by T-cells in the earliest stage of autoimmunity. This phenomena may then drive the autoimmune response. The hypothesis is that HLA alleles define the specificity of immune attack by presentation of specific epitopes of GAD 65. To investigate this problem immortalized B cells capable of presenting naturally processed GAD 65 will be developed. The immortalized B cells will be used to identify and characterize potential autoreactive T cell epitopes in relation to IDDM. Once the repertoire of naturally processed epitopes are defined, a series of synthetic peptides will be used to probe various characteristics of HLA antigen binding clefts and T-cell receptor activation. These results should highlight differences in length, sequence, and anchor residues of presented GAD 65-derived epitopes that may be important in diabetogenesis. Dr. Joseph Avruch, Chief of the Diabetes Unit at MGH, will serve as phase II clinical sponsor. The thrust of phase II (pending results from phase I) will be to a) further characterize important epitopes and their T-cell interaction with an eye towards developing specific antagonists and, b) investigate further the pathways important in processing antigen. The candidate plans to use this system as a generalized model for antigen processing and presentation.